PXD026263-1

PXD026263 is an original dataset announced via ProteomeXchange.

Title	Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function
Description	Transcription factors harbour defined intrinsically disordered regulatory regions, which raises the question of how they mediate binding to structured co-regulators and how this regulates activity. Here, we present a detailed molecular regulatory mechanism of Forkhead box O4 (FOXO4) by the structured transcriptional co-regulator β-catenin. We find that the largely disordered FOXO4 C-terminal region, which contains its transactivation domain binds β-catenin through two defined interaction sites, and this is regulated by combined PKB/AKT- and CK1-mediated phosphorylation. Binding of β-catenin competes with the auto-inhibitory interaction of the FOXO4 disordered region with its DNA-binding forkhead domain, and thereby enhances FOXO4 transcriptional activity. Furthermore, we show that binding of the β-catenin inhibitor protein ICAT is compatible with FOXO4 binding to β-catenin, suggesting that ICAT acts as a molecular switch between anti-proliferative FOXO and pro-proliferative Wnt/TCF/LEF signalling. Together these data illustrate how the interplay of intrinsically disordered regions, post-translational modifications and co-factor binding contribute to transcription factor function. Highlights • The interaction network between FOXO4 and β-catenin was deciphered • FOXO4 auto-inhibition interferes with DNA binding and is counter-acted by β-catenin • FOXO4 exists in multiple conformations regulated by phosphorylation and co-factors • ICAT switches between FOXO4 and TCF/LEF transcription factors
HostingRepository	PRIDE
AnnounceDate	2022-04-15
AnnouncementXML	Submission_2022-04-15_05:08:23.265.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Harmjan Vos
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue; deamidated residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2021-05-25 22:49:12	ID requested
⏵ 1	2022-04-15 05:08:23	announced
2	2023-11-14 08:53:07	announced	2023-11-14: Updated project metadata.

10.1016/J.CELREP.2021.109446;

submitter keyword: NMR spectroscopy, Structural biology, Intrinsically disordered proteins, Post-translational modification, Phosphorylation, Wnt signalling, FOXO signalling, -catenin, ICAT, Transcription factors

Boudewijn M.T. Burgering
contact affiliation	2Oncode Institute and Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands.
contact email	b.m.t.burgering@umcutrecht.nl
lab head
Harmjan Vos
contact affiliation	University Medical Center Utrecht Dept. Molecular Cancer Research
contact email	h.r.vos-3@umcutrecht.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD026263
     1. Label: PRIDE project
     2. Name: Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function